In need of good neighbours: transcription factors require local DNA hypomethylation for target binding.

Whether and how DNA methylation influences the binding of transcription factors (TFs) to their corresponding DNA sequence motifs in vivo remains largely unresolved. In a recent publication, Schübeler and coworkers (Domcke et al, 2015) identify a few methylation-restricted TFs in mouse embryonic stem cells, including NRF1. The authors show that NRF1 binding to its motif can be outcompeted by de novo DNA methylation, suggesting that methylationsensitive TFs rely on neighbouring motifs in cis—bound by pioneer TFs—to ensure local hypomethylation.